Despite a benign public perception, marijuana use disorders represent a significant public health problem. Because the only existing evidenced-based clinical strategies for treating marijuana dependence are behavioral interventions, the development of safe and effective pharmacotherapy for marijuana dependence is an important unmet public health need. The ideal pharmacotherapy for marijuana dependence would: 1) be safe and well tolerated when administered to patients using marijuana~ 2) reduce marijuana intake and promote abstinence~ and 3) treat the symptoms of marijuana withdrawal. The development of safe and effective pharmacotherapy's for marijuana dependence is an important unmet public health need. Quetiapine, an effective atypical antipsychotic that acts by blocking serotonin type 2A, dopamine type 2, histamine type 1, and adrenergic receptors, is a promising treatment for substance use disorders. In animal models, quetiapine blocks the enhancement of reward by cocaine, which is likely due to its actions on both dopamine and non-dopamine neurotransmission. Clinical studies of quetiapine have shown benefit for the treatment of alcohol and cocaine use disorders. Conceptually, the clinically prominent effects of quetiapine, namely sedation, anxiolysis, mood stabilization and appetite stimulation, are a good match for the symptoms of marijuana withdrawal. Most importantly, an open-label dose-finding study of quetiapine for the treatment of marijuana dependence conducted by our research group determined that quetiapine was well-tolerated and associated with reductions in marijuana use indicating that it is a promising agent deserving of further study in marijuana-dependent outpatients. The proposed research project is a randomized double-blind placebo-controlled clinical trial to evaluate the efficacy of quetiapine for the treatment of marijuana dependence over a 12-week period. All participants will receive Medical Management, a medication adherence focused psychosocial intervention that facilitates compliance with study medication and other study procedures, promotes abstinence from marijuana and other substances, and encourages mutual-support group attendance. All participants will receive voucher incentives for compliance with study visit attendance, returning study medication bottles, and completing other study procedures, with the objective of achieving a highly compliant sample. The goal of this phase II clinical trial is to build on our promising open-label pilot study results and examine th efficacy of quetiapine on participants' marijuana consumption under placebo-controlled double-blind conditions using an abstinence-initiation model, where participants will be using marijuana regularly at study entry, reduce their use, and then achieve abstinence. The specific aims of the projects are to determine whether quetiapine is superior to placebo in 1) reducing marijuana use and 2) achieving abstinence. PUBLIC HEALTH RELEVANCE: Marijuana dependence is the most prevalent illicit drug dependence in the U.S. and is a significant public health problem responsible for substantial health and economic costs. There are no available medication treatments for marijuana dependence~ the only available evidence-based treatments are psychosocial interventions with limited efficacy. The development of effective pharmacotherapy for marijuana dependence would increase both the availability and accessibility of treatment for marijuana dependence.